Identification of novel plasminogen activator inhibitor-1 inhibitors with improved oral bioavailability: Structure optimization of N-acylanthranilic acid derivatives.

Novel plasminogen activator inhibitor-1 (PAI-1) inhibitors with highly improved oral bioavailability were discovered by structure-activity relationship studies on N-acyl-5-chloroanthranilic acid derivatives. Because lipophilic N-acyl groups seemed to be important for the anthranilic acid derivatives to strongly inhibit PAI-1, synthesis of compounds in which 5-chloroanthranilic acid was bound to a variety of highly lipophilic moieties with appropriate linkers was investigated. As the result it appeared that some of the derivatives possessing aryl- or heteroaryl-substituted phenyl groups in the acyl chain had potent in vitro PAI-1 inhibitory activity. Oral absorbability of typical compounds was also evaluated in rats, and compounds 40, 55, 60 and 76 which have diverse chemical structure with each other were selected for further pharmacological evaluation.

Abnormal microstructures of the basal ganglia in schizophrenia revealed by diffusion tensor imaging.

There has been a hypothesis that deficits in the basal ganglia-thalamic system may play an important role in the dysfunctional goal-directed behaviour in schizophrenia. By using diffusion tensor imaging, we measured fractional anisotropy (FA) values in the basal ganglia-thalamic system in 42 schizophrenics and 42 matched controls to investigate microstructural tissue alterations in the basal ganglia-thalamic system in schizophrenia. Schizophrenics had significantly lower FA values in the bilateral globus pallidus and left thalamus compared to controls, suggesting that schizophrenics might have microstructural abnormalities in globus pallidus and thalamus. These data support the notion that myelination abnormalities in basal ganglia-thalamic system are related to the pathophysiology of schizophrenia.